Two HCV Meds are Better than One for Pharmasset

An announcement hinting at the possibility of an all-oral hepatitis C treatment had researchers abuzz last week. Pharmasset, a Princeton, NJ company specializing in antiviral discovery, alluded to upcoming conference data that suggested a combination of ribavirin (a generic antiviral) and Pharmasset's experimental pill PSI-7977 lowered viral counts to near-undetectable levels in a ten-patient trial (kudos to Adam Feuerstein of The Street for initial reports. . . here at The Haystack, editor Lisa Jarvis has also tracked HCV drug development for some time now). Hepatitis C virus (HCV) is a chronic liver virus with an estimated 180 million infected worldwide. Two relatively new extermination options are available: Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), approved by the FDA ten days apart last year. Unfortunately, though both drugs are administered orally, each requires co-administration of injected interferon, which can cause severe fatigue and flu-like symptoms. Both oral drugs inhibit the same enzyme: the NS3 protease, which drags down a patient’s immunity and helps the virus to produce new copies of its proteins. In contrast, the ribavirin and PSI-7977 combination involves no injections, making it easier for patients to follow the appropriate medication schedule, and lessening side effects. The PSI compound also clips a different target: NS5B polymerase, an RNA enzyme that helps viral genetic replication. In addition, the PSI-7977 is “pan-genotypic,” meaning it inhibits several genetically different strains of HCV.  A 2010 article (J. Med. Chem. 2010, 53, 7202) details the full story of PSI-7977’s synthesis. Notice anything interesting? It’s really a nucleotide strapped on to a P-chiral prodrug, a “protected” substance the body later converts to the active drug species. This P-chiral motif is seen more often in asymmetric phosphine ligands (compounds that stick to metal catalysts during reactions to modify catalyst activity) than in drug development – often chemists install drug chirality at carbon or sulfur instead. The initial drug lead was actually a mixture of both phosphorus enantiomers (“Sp” and “Rp”), until process chemists realized they could selectively crystallize out the more potent “Sp” product. In the meantime, Pharmasset scientists haven’t stopped pushing their HCV portfolio forward: a recent paper (J. Org. Chem., 2011, 76, 3782) details a new lead: PSI-352938, a cyclic phosphate prodrug attached to a purine-fluororibose nucleotide warhead. The team credits this new prodrug design with a 10-100-fold increase in potency over the “naked” adenine drug for NS5B RNA polymerase inhibition. PSI-352938 recently completed a multiple ascending dose Phase I trial, in which a daily 200 mg dose brought HCV titres down below the detection limit in 5 of 8 patients. 

Author: See Arr Oh

See Arr Oh is a Ph.D. chemist working in industry

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  1. You can’t say it has minimal side effects. Almost all the people who have been taking it and on the hepatitis c boards (please actually check those out for info) all had fatigue and migraines which is to be expected. They’ve been checking aggressively on the liver function tests. We’re just hoping that this time around that it will have no long term side effects since so many companies have done the phase 2 only to peter out by the phase 3.

  2. Grace: Thanks for writing in. Please note that I did not write “minimal side effects,” but simply “lessened” as this is the language used in most of the study reports.

    I’ve looked through the and message boards, as well as Hepatitis Central and WebMD, and I must say that most of the posters there seem upbeat about the treatment, and don’t mention migraines as you’ve suggested, simply mild headaches and non-cardiac chest pain.

    If you have access to contrasting information that could improve future blog posts, please send it to me at

  3. I am currently in Pharmassett’s Atomic Study. I’m in the 12 week arm of psi 7977, peg-int & ribe. I have had the typical peg-int & ribe side effects. Some of the other participants have had no side effects. I has EVR in one week, an over 5 log drop to undetectable. This is the first time my viral load has ever been below 1 million, (about 20 years) After one week my liver enzymes were in normal range for the first time in almost 40 years. All the others at this study site have cleared by week 2-3. I think that Pharmasett will have a 12 week or shorter non peg-int & ribe cure within 2-3 years

  4. @richard: Wow, thanks for writing in….keep up the good fight. I’m glad to hear things are looking up for you.

    If anyone else wants to share their personal experiences in this or any other clinical trial we write about here at The Haystack, please don’t hesitate to comment or email.